Process for the manufacturing of iodinated contrast agents

ABSTRACT

PCT No. PCT/EP96/03150 Sec. 371 Date Mar. 24, 1997 Sec. 102(e) Date Mar. 24, 1997 PCT Filed Jul. 17, 1996 PCT Pub. No. WO97/05097 PCT Pub. Date Feb. 13, 1997A process for the preparation of compounds of general formula (I)    &lt;IMAGE&gt;  (I)  characterized in that the corresponding derivatives of general formula (II)    &lt;IMAGE&gt;  (II)  are reacted with the compounds of general formula (III)    &lt;IMAGE&gt;esidue of a sulfonic acid or a -N+(R9)3 cation wherein R9 is a (C1-C6) alkyl group and R1, R2, R3, R4, R5 R6 R7 and R8 are as herein defined.

This application is a 371 of PCT/EP96/03150 filed Jul. 17, 1996.

This invention refers to a new synthetic process especially for themanufacturing of derivatives of diamides of5-alkoxy-2,4,6-triiodo-1,3-benzenedicarboxylic acids of general formula(I) ##STR4## wherein R₁, R₂, R₃, R₄, which can be the same or differentare, independently, H or a linear or branched (C₁ -C₁₀) alkyl group,optionally substituted by 1-6 hydroxy and/or alkoxy groups, or apolyoxyalkyl group comprising from 1 to 10 oxygen atoms and from 3 to 30carbon atoms, or R₁ and R₂ or R₃ and R₄, taken together, form a (C₂ -C₈)chain optionally interrupted by one or more N, O, S atoms;

R₅ is the group ##STR5## R₆ and R₈, which can be the same or differentare, independently, H or a (C₁ -C₆) alkyl, hydroxyalkyl, alkoxyalkyl oralkoxyhydroxyalkyl group,

R₇ is H or a (C₁ -C₃) alkyl, hydroxyalkyl or alkoxyalkyl group,

characterized in that the corresponding derivatives of general formula(II) ##STR6## wherein R₁, R₂, R₃ and R₄ are as previously described andthe hydroxy group on the benzene ring can be also present as salt of analkali metal or alkaline-earth metal or a (C₂ -C₆) trialkylamine, arereacted with the compounds of general formula (III) ##STR7## Z ishalogen atom or a reactive residue of a sulfonic acid or a cation --N⁺(R₉)₃ wherein R₉ is a (C₁ -C₆) alkyl group and

R₆ R₇ and R₈ are as previously described.

The preparation of the compounds of general formula (I) has beenpreviously described in patent EP 185130, which describes the synthesisof the above compounds starting from phenol precursors or from theirsalts according to Scheme 1. ##STR8##

The above patent foresees the reaction of the phenol groups in the freeform or the reaction in the salified form with alkali or alkaline-earthmetals with a reactive compound R₅ '--Z', preferably containing analkoxycarbonylalkyl group and a reactive group Z', with the same meaningfor Z in this invention and the successive transformation of the estergroup into amido group, by reaction with ammonia or with differentlysubstituted amines.

The resulting products of formula 2 can be useful also as intermediatesas described in patent EP 365541, for the preparation of X-ray contrastmedia by Smiles rearrangement.

Differently from patent EP 185130, the process of this invention,foresees only one step for the production of the desired product, i.e.the direct reaction of phenol precursors with a reactive compoundalready containing the desired amido group, as from Scheme 2. ##STR9##

The use of an amido derivative in the reaction of nucleophilicsubstitution to give derivatives of general formula (I) instead of anester derivative, as described in patent EP 185130, leads to aconsiderable decrease in the number of synthetic steps required toobtain the final compounds of general formula (II).

The application of the process of this invention is particularlyinteresting for the preparation of an intermediate in the synthesis ofS-N,N'-bis 2-hydroxy-1-(hydroxymethyl)ethyl!-5-(2-hydroxy-1-oxopropyl)amino!-2,4,6triiodo-1,3-benzenedicarboxamide,commonly known as IOPAMIDOL, which is one of the world best-seller inthe field of non-ionic X-ray contrast media.

The synthesis method described in EP 365541, foresees the formation ofintermediate 3, according to the procedure described in the alreadycited EP 185130, followed by Smiles rearrangement, as shown in Scheme 3.##STR10##

A more straightforward preparation for iopamidol can be carried out bythe sequence of reactions shown in Scheme 4 and described in Examples 1,2 and 4. ##STR11##

More generally, in order to carry out the process of this invention, thesalts of phenol derivatives of general formula (II) are particularlysuitable for the reaction of etherification, in particular their sodium,potassium and calcium salts.

The reactive group Z in compounds of general formula (III) is asdefinition a halide Cl, Br and I, or a reactive residue of a sulfonicacid (for instance methanesulfonyloxy (MeSO₂ O⁻), benzenesulfonyloxy(PhSO₂ O⁻), nitrobenzenesulfonyloxy (p-NO₂ PhSO₂ O⁻), toluensulfonyloxy(TsO⁻), and so on), preferably toluenesulfonyloxy, or a N⁺ (R₉)₃ cationwherein R₉ is as previously defined.

Particularly preferred are the following reaction conditions for theprocess of this invention:

the sodium salt of the phenol compound of formula (II);

the stoichiometric ratio compound of formula (III)/compound of formula(II) is equal to 2;

the formation of a ether bond between the compounds of general formula(II) and the compounds of general formula (III) is carried out at atemperature comprised between room temperature and 120° C., preferably60°-100° C.;

the use of protic and dipolar aprotic solvents, preferably water, H₂O/EtOH mixture, dimethylacetamide (DMA), methyl cellosolve and ethylcellosolve.

The ether bond formation between the compounds of formula (II) and thoseof formula (III) implies a nucleophilic substitution reaction whichinvolves inversion of configuration when in the compound of generalformula (III) a chiral carbon is present.

In view of the results of this invention, we can desume that,considering the same leaving group in the compound of general formula(III), as the protonating ability of the solvent increases (i.e. thecapacity of the solvent of donating protons for the formation ofhydrogen bonding), the most optically pure product is obtained.

The resulting amides can be used in Smiles rearrangement reactions,under the conditions cited in patent EP 365541 to obtain diagnosticcompounds, such as Iopamidol (Examples 1, 3 and 4).

The isolation of the compounds of general formula (I) is carried outaccording to the methods known in the practice of organic chemistry.Often, through the use of ion exchange resins, or electrodialysis ortangential filtration techniques using filtration membranes, the salts,bases or acids should be removed from the resulting water-solublecompounds.

The following examples are meant for the illustration of the bestpossible experimental conditions in order to carry out the process ofthis invention.

    ______________________________________                                        EXAMPLE 1                                                                      ##STR12##                                                                     ##STR13##                                                                     ##STR14##                                                                    R = CONHCH(CH.sub.2 OH).sub.2                                                                   Lactate/ Recovery                                                   Solvent   fenate   yield in 2                                                                           Optical                                                                             Chemical                              Z'      1 → 3                                                                            (mol/mol)                                                                              steps  purity                                                                              purity                                ______________________________________                                        1    TsO    DMA       2      40     67    96                                  2    TsO    Methylcell.                                                                             2      40     96    99                                  3    TsO    H.sub.2 O/EtOH                                                                          2      56     98    99                                  4    MsO    Methylcell.                                                                             2      30     84    98                                  5    MsO    Ethylcell.                                                                              2      42     88    98                                  6    MsO    H.sub.2 O/EtOH                                                                          2      40     94    97                                  7    MsO    H.sub.2 O 2      56     94    98                                  8    Cl     Methylcell.                                                                             2      33     20    98                                  9    Cl     Methylcell..sup.a                                                                       2      31     13    95                                  10   Cl     H.sub.2 O 2      40     88    99                                  ______________________________________                                         .sup.a : with the addition of KI (0.15 mol equiv. with respect to             phenoxide) as catalyst                                                   

EXAMPLE 2 (S)-5-(2-amino-1-methyl-2-oxoethoxy)-N,N'-bis2-hydroxy-1-(hydroxymethyl)ethyl!-2,4,6-triiodo-1,3-benzenedicarboxamide##STR15##

To a solution of 21.8 g of N,N'-bis2-hydroxy-1-(hydroxymethyl)ethyl!-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamidesodium salt (prepared according to the procedure described in patent EP185130) (0.03 mol) in 70 mL of methyl cellosolve, heated to 80° C., 14.6g of R-2- (4-methylphenyl)sulfonyl!oxy!propanamide (prepared accordingto the procedure described in Markert, F. Chem. Ber. 1927, 60, 2456)(0.056 mol) are added and the resulting mixture is kept under stirringin the same conditions for 8 h. After removing methyl cellosolve byevaporation under reduced pressure, the oily residue is treated with CH₂Cl₂ (2×250 mL). The solid, filtered and dried is dissolved in abs. EtOH(190 mL) and after filtration of sodium p-toluensulfonate, the solutionis concentrated to dryness. The treatment is repeated with abs. EtOH(150 mL) and after evaporation the resulting residue is crystallizedfrom abs. EtOH (75 mL). 10.5 g of the desired product (0.0135 mol) arerecovered.

Yield: 45% m.p.: 110° C.

α!^(D) ₂₀ =-22.90° (c 5%, CH₃ OH)

TLC: silica gel plate 60F 254 Merck

Eluent: CHCl₃ :CH₃ OH:NH₄ OH 25%=6:3:1

Detector: soluble starch and UV light R_(f) =0.22

¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the structure.

EXAMPLE 3 Preparation of IOPAMIDOL starting from(S)-5-(2-amino-1-methyl-2-oxoethoxy)-N,N'-bis2-hydroxy-1-(hydroxymethyl)ethyl!-2,4,6-triiodo-1,3-benzenedicarboxamide##STR16##

To 10.1 g of (S)-5-(2-amino-1-methyl-2-oxoethoxy)-N,N'-bis2-hydroxy-1-(hydroxymethyl)ethyl!-2,4,6-triiodo-1,3-benzenedicarboxamide(prepared according to the procedure described in EXAMPLE 2) (0.013 mol)dissolved in 50 mL of MeOH, and maintained under reflux, are swiftlyadded 56 mL of KOH 1N in MeOH (0.056 mol) then the mixture is refluxedfor 2 h. After cooling to room temperature, MeOH is removed by vacuumdistillation. The solid residue is diluted in water (100 mL) andpercolated on cation exchange resin Amberlite® IR 120 and anion exchangeresin Duolite® A 30B eluted with water. After evaporation of the aqueoussolution the residue is crystallized from EtOH (35 mL) to give 8.9 g ofthe desired product (0.0114 mol).

Yield: 88%

Sample purity: 99.8%

α!²⁰ ₄₃₆ =+137.00° (c=1.25% w/v as Cu(II) complex), optical purity 96%literature α!²⁰ ₄₃₆ =+142.28°±0.13°!

¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the structure.

EXAMPLE 4 Preparation of IOPAMIDOL starting from N,N'-bis2-hydroxy-1-(hydroxymethyl)ethyl!-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide

To a solution of 17.20 g of N,N'-bis2-hydroxy-1-(hydroxymethyl)ethyl!-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamidesodium salt (prepared according to the procedure described in patent EP185130) (0.0236 mol) in 60 mL of a H₂ O/EtOH 4/1 mixture, heated to 80°C., 11.5 g of R-2- (4-methylphenyl)sulfonyl!oxy!propanamide (preparedaccording to the procedure described in Markert, F. Chem. Ber. 1927, 60,2456)(0.056 mol) are added and the resulting mixture is kept understirring for 8 h. After removal of the solvent by evaporation underreduced pressure, the oily residue is treated with CH₂ Cl₂ (2×250 mL).The solid, filtered and dried, is dissolved in abs. EtOH (190 mL) andafter filtration of sodium p-toluensulfonate, the solution isconcentrated to dryness. To the solution of the residue (70 mL MeOH)refluxing, 81 mL on 1N KOH in MeOH (0.0811) are swiftly added and theheating is kept during 2h. After cooling to room temperature, MeOH isremoved by vacuum distillation. The residual solid is diluted in water(100 mL) and percolated on a cation exchange resin Amberlite® IR 120 andon an anionic exchange resin Duolite® A 30B eluted with water. Afterevaporation of the aqueous solution the residue is crystallized fromEtOH (50 mL) to give 10.2 g of the desired product (0.0131 mol).

Yield: 56% yield in two steps

α!^(D) ₂₀ =+138.88° (c=1.25% w/v as Cu(II) complex), optical purity 96%literature α!²⁰ ₄₃₆ =+142.28°±0.13°!

¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the structure.

We claim:
 1. A process for the preparation of compounds of generalformula (I) ##STR17## wherein R₁, R₂, R₃, R₄, which can be the same ordifferent, are, independently, H or a linear or branched (C₁ -C₁₀) alkylgroup, optionally substituted by 1-6 hydroxy and/or alkoxy groups, or apolyoxaalkyl group comprising from 1 to 10 oxygen atoms and from 3 to 30carbon atoms,R₅ is the group ##STR18## wherein R₆ and R₈ which can bethe same or different, are, independently, H or a (C₁ -C₆) alkyl,hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl group, R₇ is H or a (C₁-C₃) alkyl, hydroxyalkyl or alkoxyalkyl group,characterized in that thecorresponding derivatives of general formula (II) ##STR19## wherein R₁,R₂, R₃ and R₄ are as previously defined and the hydroxy group on thebenzene ring can be also present as salt of alkali metal oralkaline-earth metal or a (C2-C6) trialkylamine, are reacted with thecompounds of general formula (III) ##STR20## wherein Z is halogen atomor a reactive residue of a sulfonic acid or a --N⁺ (R₉)₃ cation whereinR₉ is a (C₁ -C₆) alkyl group and R₆ R₇ and R₈ are as previously defined.2. A process according to claim 1, wherein the compound of formula (II)is in the form of sodium salt.
 3. A process according to claim 1,wherein the stoichiometric ratio of the compound of formula (III) andthe compound of formula (II) is equal to
 2. 4. A process according toclaim 1, wherein the ether bond formation between the compounds ofgeneral formula (II) and the compounds of general formula (III) iscarried out at a temperature comprised between room temperature and 120°C.
 5. A process according to claim 1, wherein the reaction solvent isselected from the group consisting of protic solvents and dipolaraprotic solvents, preferably H₂ O, H₂ O/EtOH mixture, dimethylacetamide(DMA), methyl cellosolve and ethyl cellosolve.